Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that bears a close histological resemblance to rheumatoid arthritis of humans. M. arthritidis-induced arthritis has been extensively studied as a model for arthritides caused by infectious agents and also as a model for examining the role(s) of superantigens in the development of autoimmunity. All strains of M. arthritidis are thought to produce the superantigen MAM, but many MAM-producing strains are relatively avirulent. Thus, factors in addition to MAM must be required for the development of arthritis. We have recently identified a spontaneous mutant (strain 158-1) of M. arthritidis that is avirulent and is rapidly cleared from the mouse in the first few hours of infection. The mutant has a major antigenic difference when compared to the virulent parent strain. The parent 158 strain has a protein designated MIA (mycoplasma immunodominant antigen) that has 23 copies of a 8-amino acid tandem repeat sequence. In its place, 158-1 has the same protein (the ORF 619 gene product) but with 31 tandem repeats. A primary goal of this proposal is to determine whether MAM and MIA are virulence factors for the development of arthritis. The identification of M. arthritidis virulence factors is a first step towards fulfillment of the long-range goal of understanding the pathogenesis of mycoplasma-induced arthritis. Factors analogous to MAM and MIA may be prevalent in microorganisms that cause arthritis in humans, and these factors may be important as vaccine candidates and as targets for drug design. We have in collaboration with TIGR determined the complete genome sequence of this species, which will assist us in the construction of mutants of M. arthritidis in which genes of interest (e.g., encoding MAM and MIA) have been disrupted (Specific Aim 1). Aim 2 is to complement the mutants generated in Aim 1 and compare the virulence of the mutants and the complemented mutants, thus determining whether MAM and MIA are virulence factors. Aim 3 is to continue our studies on 158-1 to determine why it is rapidly cleared from infected mice. An understanding of the inability of 158-1 to resist host defenses may offer an unique opportunity to explore interactions between the mycoplasma and innate immunity.